1. Field of the Invention
This invention relates to prostacyclin (PGI.sub.2) analogues which are used as antithromboic and antiulcer drugs in the field of medicines. In more detail, this invention relates to the compounds represented by the general formula (I) or their salts, which have prostacyclin (PGI.sub.2)-like inhibitory activity against platelet agglutination and antiulcer activity. ##STR2## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is lower alkyl, lower alkenyl, lower alkynyl, lower aralkynyl, lower alkyloxy, arylthio, or cyano; R.sub.3 and R.sub.4 each is hydrogen or hydroxy-protecting group; R.sub.5 is straight or branched alkyl which may be substituted with heterocycle, straight or branched alkynyl, or cycloalkyl; the wavy line indicates R- or S-configuration, or their mixture:
PGI.sub.2 produced mainly in the vascular cell or leukocytes as follows. Phospholipase A.sub.2 activated by chemical or physical stimulation of the vascular cell, accelerates release of arachidonic acid which is converted into PGI.sub.2 by the action of cyclooxygenase and PGI.sub.2 synthetase. PGI.sub.2 has a potent inhibitory activity against platelet agglutination and vasodilative activity and is used an antiplatelet agent for patients who have been treated with artificial dialysis or pump-oxygenator. As the other clinical applications of PGI.sub.2, the applications to thrombotic diseases such as peripheral circulatory insufficiency, e.g., vibration disease, collagen diseases, Buerger disease, and arteriosclerosis obliterans; ischemic heart disease, e.g., angina pectoris and myocardial infarction; and disturbance of cerebral circulation, e.g., cerebral thrombosis, cerebral embolis and cerebral infarction, are expected. However, PGI.sub.2 also has several problems; for example, it is chemically unstable and has hypotensive activity, which is undesirable for antithromboic drugs. Therefore, it has been desired that the chemically stable PGI.sub.2 analogues having more potent platelet agglutination inhibitory activity and higher selectivity of the action are developed.
The present inventors have prepared the prostacyclin analogues represented by the general formula (I), and found that these novel compounds have a potent activity as PGI.sub.2 receptor agonists and are chemically stable. The present invention is based upon these findings.
2. Description of the Prior Art
Thrombosis is induced with occurrence of hemangioendothelium injury or inflammation, alteration of blood flow volume, or raise of blood coagulation ability. A white thrombus, often induced by Buerger disease, arteriosclerosis obliteran and so on, is also known as conglutination thrombus which is generated by gathering of platelets, leukocytes, fibrin, or erythrocytes on the injury, ulcer or rough surface of the intima, obliterates or strangulates the lumen, readily adheres to the wall of artery and causes the organic diseases. In the vein, alteration of the blood flow volume and congestion of the blood flow which are provoked by many causes generate intravascular cagulation to form red thrombus. Usually, the red thrombus is adhered to the surface of the white thrombus to gradually induce the obliteration extending over a wide area. When the main artery is rapidly blocked by thrombus, a strong disturbance of peripheral circulation is caused accompanied by the necrosis of tissue. Thus, it is thought that the agglutination activity of platelet is an important factor in vascular diseases such as thrombosis and arterial sclerosis. Therefore, it has been recognized that the administration of antithromboic drugs, especially the drugs which possess inhibitory activity against platelet agglutination will be efficacious for the prevention or treatment of those vascular diseases. In addition to the conventional antithromboic drugs such as heparin and coumarin compounds, a certain type of prostaglandins (hereinafter abbreviated to PG) are known to have a potent inhibitory activity against platelet agglutination. From these facts, prostaglandin derivatives have attached public attention as antithromboic drugs. For example, PG analogues which act as agonists of the receptor of PG E.sub.1 and I.sub. 2, having potent inhibitory activity against platelet agglutination and vasodilating activity, have been developed as well as, inhibitors which inhibit synthesis of thromboxane A.sub.2 adversely acting to PGI.sub.2. As the PGI.sub.2 analogues, Hoe-892 [B. A. Scholkens et. al., Prostaglandins Leukotrienes. Med., 10, 231-256, (1983)], OP-41483 [P. G. Adaikan et. al., Prostaglandins Leukotrienes. Med., 10, 53-64, (1983)], ZK-36374 [J. J. F. Belch et. al., Prostaglandins, 28, 67-77, (1984)] Nitrilo-PGI.sub.2 [R. R. Gorman et. al, Prostaglandins, 19, 2-14, (1980)], and 9-substituted carbacyclin analogue [P. A. Aristoff et. al., J. Org. Chem., 48, 5341-5348, (1983)] can be exemplified.